Joe Betts-LaCroix: Inside Retro Biosciences — Reprogramming, Autophagy & the Race to Clinical Trials | Frameshifts Episode #13

Most longevity talk is still stuck within two bad schools of thought. On one side, weak-sauce incrementalism: supplements, vibes and tiny effect sizes. On the other, immortality rhetoric that asks you to throw out the data altogether. Joe Betts-LaCroix has very little patience for either. He’s the co-founder and CEO of Retro Biosciences, one of the most ambitious longevity companies in the world. Launched with an initial $180 million of capital from Sam Altman’s personal wealth, the company has since raised new round led by 4P Capital at a $1.8 billion valuation. Retro’s mission is to add ten healthy years to human life by going after the cellular mechanisms of aging directly. Betts-LaCroix is an unlikely person to be running a longevity company. He left school with a D average and spent six years in a shared house with a “bunch of musicians and artists and weirdos”, doing electronics work to pay rent. That somehow became biophysics at Harvard, MIT and Caltech, then building the world’s smallest personal computer (OQO, acquired by Google), and later founding an automated animal-research company (Vium, acquired by Recursion), before landing on the question he couldn’t walk away from, which is why we age and what we can actually do about it. A lot of our conversation is about what a serious longevity biotech company looks like once you strip the noise away. We dig into how Retro chose its three core programs, autophagy, partial reprogramming and blood stem cell replacement, out of an initial six. We talk about how the company walked away from their blood plasma program despite promising early data, and how their liver reprogramming results, dramatic as they were in mice, became commercially unviable once GLP-1 drugs reshaped the entire liver-disease market. Their first drug, a small-molecule autophagy therapy aimed at neurodegeneration, has since begun dosing patients in a Phase I trial in my home country of Australia. Then we go deep on GPT-4b micro, the protein-design model Retro built with OpenAI. Joe lays out what it actually is and isn’t, how it can rewrite up to 80% of a protein’s amino acids while still preserving fold and function, and why the redesigned Yamanaka factors it produced have already made their way into FDA submissions. It’s striking to me that this model (among several others in its class) keeps proposing designs no human would ever have come up with, and that general-purpose protein generation carries a biosafety tension Joe doesn’t try to dodge. From there, our conversation opens up into the bigger questions: why aging may not need to be formally recognized as a disease for meaningful therapies to win approval, what it takes to build a company around a problem this hard, and, near the end, what happens to human ambition and our sense of time when people stop living only for tomorrow. In this episode, we cover: \* Why the target isn’t immortality but ten additional healthy years \* Why one of its first clinical programs targets autophagy in neurodegeneration \* How partial reprogramming evolved from whole-body proof of concept toward tissue- and cell-type-specific intervention \* Why Retro walked away from a promising liver reprogramming program despite dramatic mouse data \* How GPT-4b micro works as a protein-design model, and why it’s more than “an LLM for Yamanaka factors” \* Why protein design may unlock improved versions of our own endogenous maintenance machinery \* How Joe thinks about regulation, aging endpoints, and what will eventually force the FDA to adapt \* Why meaningful missions tend to produce stronger companies and stronger teams \* Why he sees longevity not as a billionaire side quest, but as one of the most important things a civilization could work on The most important problems in biology might also, if you’re careful about which ones you take on, turn out to be the solvable ones. GUEST INFORMATION: \* Joe Betts-LaCroix, Co-Founder & CEO, Retro Biosciences \* Retro Biosciences \* OpenAI x Retro Biosciences, GPT-4b micro \* Defining a longevity biotechnology company (Nature Aging) \* X (Twitter): @bettslacroix \* LinkedIn CONNECT WITH US: \* Website \* Substack \* YouTube \* X (Twitter) \* LinkedIn \* TikTok Get full access to Frameshifts with Benjamin Arya at frameshifts.bio/subscribe